This project is concerned with characterizing and improving the delivery of pharmacologic and diagnostic agents to the central nervous system. Previously developed theory and experimentation have indicated the potential for achieving large scale spread of macromolecules in brain by high flow microinfusion. The ability of a floating silica cannula to reproducibly deliver homogeneous concentrations of macromolecular agents (kurtosis =-1.1) over multicentimeter distances in the pig and primate spinal cords has been demonstrated. Longitudinal distribution is aided by the anisotropic transport along white matter tracts. The floating silica cannula also was shown capable of delivering homogeneous concentrations of macromolecular agents to the perineural spaces within the epineurium. Agent followed the parallel arrangement of axonal fibers and filled up to 6.8 cm long segments of nerve without introducing neurologic deficit. Studies into the factors that determine the occurrence and magnitude of backflow around infusion cannulae during the direct interstitial infusion of brain tissue were completed. Experiments measured the effects on focal delivery of cannula radius, volumetric infusion rate, infusate concentration, and sealing time. Theoretical prediction of the percentage of mass overflow from a caudate target region into surrounding white matter as a function of flow rate compared well with experimental measurement. Theoretical scaling laws were also upheld. The feasibility and clinical efficacy of convective drug delivery to accomplish targeted lesioning was also demonstrated by the selective ablation of the globus pallidus interna with quinolinic acid in an MPTP-induced model of non-human primate parkinsonism. Accurate targeting was accomplished with a mathematical model of infusion into brain tissue using recently measured transport and metabolic parameters for the drug determined by multiple isotope microdialysis. (This is a continuation of Intramural Research Project Z01-RR-10353-07 BEI.)